5-35871136-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_002185.5(IL7R):c.460C>T(p.His154Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000869 in 1,611,658 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000087 ( 3 hom. )

Consequence

IL7R
NM_002185.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 4.46

Publications

6 publications found

Variant links:

Genes affected

IL7R (HGNC:6024): (interleukin 7 receptor) The protein encoded by this gene is a receptor for interleukin 7 (IL7). The function of this receptor requires the interleukin 2 receptor, gamma chain (IL2RG), which is a common gamma chain shared by the receptors of various cytokines, including interleukins 2, 4, 7, 9, and 15. This protein has been shown to play a critical role in V(D)J recombination during lymphocyte development. Defects in this gene may be associated with severe combined immunodeficiency (SCID). Alternatively spliced transcript variants have been found. [provided by RefSeq, Dec 2015]

IL7R Gene-Disease associations (from GenCC):

immunodeficiency 104
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
Omenn syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
T-B+ severe combined immunodeficiency due to IL-7Ralpha deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

IL7R links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000854 (13/152194) while in subpopulation EAS AF = 0.00192 (10/5198). AF 95% confidence interval is 0.00104. There are 1 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL7R	NM_002185.5 link	c.460C>T	p.His154Tyr	missense_variant	Exon 4 of 8	ENST00000303115.8	NP_002176.2	P16871-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IL7R	ENST00000303115.8 link	c.460C>T	p.His154Tyr	missense_variant	Exon 4 of 8	1	NM_002185.5	ENSP00000306157.3	P16871-1
IL7R	ENST00000506850.5 link	c.460C>T	p.His154Tyr	missense_variant	Exon 4 of 6	2		ENSP00000421207.1	P16871-3
IL7R	ENST00000514217.5 link	n.460C>T		non_coding_transcript_exon_variant	Exon 4 of 6	2		ENSP00000427688.1	B8YG18

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000796

AC:

AN:

251252

AF XY:

0.0000442

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000870

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.0000870

AC:

127

AN:

1459464

Hom.:

Cov.:

AF XY:

0.0000620

AC XY:

AN XY:

726220

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33428

American (AMR)

AF:

0.0000224

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00154

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1109798

Other (OTH)

AF:

0.000995

AC:

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.000131

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00192

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000494

AC:

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Immunodeficiency 104

Uncertain:1

Oct 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 154 of the IL7R protein (p.His154Tyr). This variant is present in population databases (rs199727195, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with IL7R-related conditions. ClinVar contains an entry for this variant (Variation ID: 134525). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt IL7R protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

T;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.062

MetaRNN

Uncertain

0.49

T;T

MetaSVM

Uncertain

-0.17

MutationAssessor

Uncertain

2.3

M;M

PhyloP100

4.5

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.95

N;N

REVEL

Uncertain

0.44

Sift

Benign

0.14

T;T

Sift4G

Benign

0.14

T;T

Polyphen

1.0

D;.

Vest4

0.57

MutPred

0.82

Gain of methylation at K158 (P = 0.0885);Gain of methylation at K158 (P = 0.0885);

MVP

0.93

MPC

0.069

ClinPred

0.12

GERP RS

5.6

Varity_R

0.47

gMVP

0.38

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over